17belta-(substituted-oxy)-3-oxygenated-5alpha-androst-1-enes



United States Patent 3,352,853 17,6-(SUBSTITUTED-0XY)-3-OXYGENATED-Sa-ANDROST-l-ENES Paul M. Klimstra, Northbrook, Ill., assignor to G. D.Searle & Co., Chicago, [1]., a corporation of Delaware No Drawing. FiledMay 13, 1965, Ser. No. 455,602 Claims. (Cl. 260-23955) This applicationis a continuation-in-part of my copending application Ser. No. 208,954,filed July 10, 1962, now Pat. No. 3,257,428.

The present invention is concerned with novel 17-(substituted-oxy)steroids, and, more particularly, with 17,6-(substituted-oxy)-3-oxygenated-5a-androst-l-enes of the structuralformula wherein R is a tetrahydropyran-Z-yl orp-tertiary-butylphenoxyacetyl radical and Z can be a carbonyl,B-hydroxymethylene or p- (lower alkanoyl)oxymethylene radical.

Examples of lower alkanoyl radicals therein depicted are formyl, acetyl,propionyl, butyryl, valeryl, caproyl, heptanoyl, and the branched-chainradicals isomeric therewith.

A starting material suitable for utilization in the manufacture of theinstant compounds is 17p-hydroxy-5a-androst-1-en-3 one. Reaction of thatsubstance with dihydropyran in thepresence of an acid catalyst such asptoluenesulfonic acid or hydrogen chloride results in the corresponding17,6-tetrahydropyran 2 yloxy derivative, i.e.,1713-tetrahydropyran-Z-yloxy-S oc-ElfldI'OSt-l-CI1-3-OI16,

Reduction of the instant 3-keto compounds with a suitable chemicalreducing agent results in the corresponding instant 3,8-hydroxyderivatives. For example, the reduction of17B-tetrahydropyran-Z-yloxy-Sm-androst-l-en- 3-one with lithium aluminumhydride in ether afiords17B-tetrahydropyran-2-yloxy-5a-androst-1-en-3/8-ol.

Acylation of the instant 3-hydroxy compounds with a lower alkanoic acidanhydride or halide in the presence of a suitable acid acceptor producesthe corresponding 3- (lower a1kanoyl)oxy compounds. The aforementioned175-tetrahydropyran-2-y1oxy 5a androst-1-en-3B-ol, for example, isallowed to react with acetic acid in pyridine to yield17,8-tetrahydropyran-2-yloxy-5u-androst-Len-3pol 3-acetate.

The compounds of this invention exhibit valuable pharmacologicalproperties. They are hormonal and antihormonal agents, for example, asevidenced by their anabolic, androgenic and anti-estrogenic propertiesand possess the particular advantage of low anti-fertility side eifects.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirpreparation. However, the invention is not to be construed as limitedthereby either in spirit or in scope since it will be apparent to those3,352,853 Patented Nov. 14, 1967 skilled in the art of organic synthesisthat many modifications both of materials and of methods may bepracticed without departing from the purpose and intent of thisdisclosure. Throughout the examples hereinafter set forth, temperaturesare given in degrees Centigrade C.) and relative amounts of materials inparts by weight except as otherwise noted.

Example I To a solution of 20 parts of l7p-hydroxy-5a-androst-1-er1-3-one in 30 parts of methylene chloride containing 22.2 parts ofdihydropyran is added 0.01 part of p-toluenesulfonic acid, and theresulting reaction mixture is stored at room temperature for about threedays. That mixture is then washed successively with water and 5% aqueoussodium bicarbonate, following which time it is dried over anhydrouspotassium carbonate containing decolorizing carbon. Removal of thesolvent by distillation under reduced pressure affords a yellow oilyresidue which is purified by recrystallization from aqueous methanol toatford pure 17,6-tetrahydropyran-Z-yloxy-Sa-androst-1- en-3-one, meltingat about 9496. A structural representation of this compound is shownbelow.

of about 2 hours, a solution of 25 parts of17p-tetrahydropyran-Z-yloxy-Sa-androst-1-en-3-one in 175 parts of ether..Stirring of the reaction mixture is continued at room temperature forabout 2 hours. The excess reagent is destroyed by careful addition ofaqueous acetone, and

the resulting mixture is then poured carefullyinto ice and water. Thelayers are separated, and the aqueous layer is extracted with ether. Thecombined organic solutions are then washed several times with Water,dried over anhydrous potassium carbonate containing decolorizing carbonand distilled to dryness to afford an oily residue. That crude productis purified by recrystallization first from aqueous methanol, then fromhexane to yield pure17fi-tetrahydropyran-2-yloxy-5a-androst-1-en-3,3-ol, melting at about-133. This compound is characterized also by the following structuralformula Example 3 A solution containing 15 parts of 175-tetrahydropyran-2-yloxy-5a-androst-1-en-3,B-ol, 216 parts of pyridine and 119 parts ofacetic anhydride is kept at room temperature for about 16 hours, then ispoured carefully into Water. The resulting aqueous mixture is extractedwith ether,:andthe ether layer is separated, then washed successivelywith 5% aqueous sodium bicarbonate, dilute hydrochloric acid and 5%aqueous sodium bicarbonate. Drying over anhydrous potassium carbonatecontaining decolorizing carbon affords a solution which is distilled todryness under reduced pressure to afford, as an oil,17,3-tetrahydropyran- 2-yloxy-5 a-androst-1-en-3 fi-ol 3-acetate. It ischaracterized further by infrared absorption maxima, in chloroform, atabout 2.75, 3.41, 5.78, 6.01 and 7.98 microns. This compound is furthercharacterized by the following struc- 6 HaCO- Example 4 To a solution of7.5 parts of 17fl-hydroxy-5a-androst- 1-en-3-one in 73.5 parts ofpyridine is added, at 5 with rapid stirring, 8 parts ofp-tertiary-butyl-phenoxyacetyl chloride dropwise over a period of about5 minutes. The reaction mixture is stirred at room temperature for about6 hours, then is poured carefully into ice and water. Extraction of thataqueous mixture with ether affords an organic solution which is Washedsuccessively with water, 5% hydrochloric acid, and water, then driedover anhydrous sodium sulfate containing decolorizing carbon. Removal ofthe solvent by distillation under reduced pressure affords a viscousoily residue which is extracted into benzene. The resulting organicsolution is chromatographed on silica gel and the chromatographic columnis elutedrwith. 5% ethyl acetate in benzene to afford the crude product.Recrystallization of that material from acetone results in pure17,6-(p-tertiary-butylphenoxyacet) oxy-5a-androst-1-en-3-one, melting atabout 158.5-160. It exhibits an optical rotation, in chloroform, of +41and also an ultraviolet absorption maximum at about 222.5 millimicronswith a molecular extinction coefficient 4 of about 20,000, and ischaracterized further by the following structural formula O C-CHaO- C(CH3) a Example 5 By substituting an equivalent quantity of propionicanhydride and otherwise proceeding according to the processes describedin Example 3, there is obtained17fl-tetrahydropyran-2-yloxy-5a-androst-1-en-3fl-o1 3-propionate.

What is claimed is:

1. A compound of the formula OR CH3 UNITED STATES PATENTS 2,888,4745/1959 Ringold et al 260397.45

3,167,547 1/1965 Cross 260239.55

3,200,115 8/1965 Cross 260239.55

FOREIGN PATENTS 1 ,079,040 4/ 1960 Germany.

ELBERT L. ROBERTS, Primary Examiner.

H. A. FRENCH, Assistant Examiner,

1. A COMPOUND OF THE FORMULA